1.Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to beta-secretase.
Hu B1, Xiong B, Qiu BY, Li X, Yu HP, Xiao K, Wang X, Li J, Shen JK. Acta Pharmacol Sin. 2006 Dec;27(12):1586-93.
AIM: To develop probes for detecting the binding specificity between beta-secretase and substrate, and provide reliable biological activity data for further researching encircling substrate-based inhibitors.
2.Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.
Machauer R1, Veenstra S, Rondeau JM, Tintelnot-Blomley M, Betschart C, Neumann U, Paganetti P. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1361-5. doi: 10.1016/j.bmcl.2009.01.036. Epub 2009 Jan 19.
The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.
3.Surface plasmon resonance, fluorescence, and circular dichroism studies for the characterization of the binding of BACE-1 inhibitors.
De Simone A1, Mancini F, Real Fernàndez F, Rovero P, Bertucci C, Andrisano V. Anal Bioanal Chem. 2013 Jan;405(2-3):827-35. doi: 10.1007/s00216-012-6312-0. Epub 2012 Aug 29.
The mechanism of action underlying β-secretase 1 (BACE-1) inhibition was characterized by a surface plasmon resonance (SPR) method using primary amino groups to immobilize OM99-2, a well-known highly potent peptidic BACE-1 inhibitor, on the carboxyl groups of the dextran layer of a sensor chip. The diluted BACE-1 was mixed with buffer or the test compound and the mixture was flushed through the chip. BACE-1 binding to the immobilized peptide inhibitor was quantified. This SPR method was used to identify BACE-1 inhibitor binding sites and the mechanism of action (competitive/noncompetitive) and to validate findings of fluorescence resonance energy transfer (FRET) inhibition studies. To support this, a multimethodological approach (circular dichroism and fluorescence spectroscopy) was applied in parallel to FRET inhibition studies to characterize the binding modes of peptidic and nonpeptidic BACE-1 inhibitors. Circular dichroism spectroscopy served to correlate the conformation of BACE-1 with enzymatic activity and to monitor secondary structure changes upon ligand binding.
4.Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.
Hernández-Rodríguez M1, Correa-Basurto J2, Martínez-Ramos F3, Padilla-Martínez II4, Benítez-Cardoza CG5, Mera-Jiménez E6, Rosales-Hernández MC7. J Alzheimers Dis. 2014;41(4):1073-85. doi: 10.3233/JAD-140471.
Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro.
